Human Hepatocellular Carcinomas With "Stemness"-Related Marker Expression: Keratin 19 Expression and a Poor Prognosis
Human Hepatocellular Carcinomas With "Stemness"-Related Marker Expression: Keratin 19 Expression and a Poor Prognosis
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DOI：
10.1002/hep.24559
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发表时间：
2011-11-01
期刊：
影响因子：
13.5
通讯作者：
Park, Young Nyun
中科院分区：
文献类型：
--
作者：
Kim, Haeryoung;Choi, Gi Hong;Park, Young Nyun
最近提出了一种肝细胞癌（HCC）亚型，其组织学上与普通HCC相似，但其特征在于表达“干性”相关标记。本研究对两组不同的HCC进行了大规模研究，以探讨该亚型HCC的临床病理特征和上皮间质转化（EMT）相关蛋白的表达状况。干度相关基因（e.例如，在一个实施例中，角蛋白19 [K19]、分化簇[CD] 133、上皮细胞粘附分子[EpCAM]和c-kit）和EMT相关标志物（例如，例如，在一个实施例中，snail、S100 A4、尿激酶纤溶酶原激活物受体[uPAR]、ezrin、波形蛋白、E-钙粘蛋白和基质金属蛋白酶[MMP]2）。队列2 HCC（n = 237）中K19蛋白表达与临床病理参数和K19、uPAR、VIL 2、Snail、Slug和Twist的信使RNA（mRNA）水平相关。K19、EpCAM、c-kit和CD 133阳性率分别为18.2%、35.0%、34.3%和24.8%。K19最常与至少一种其他干细胞相关标志物组合表达（92.0%）。K19阳性肝癌的大血管侵犯率和肿瘤体积均高于K19阴性肝癌（P < 0.05）。K19与EMT相关蛋白表达最显著相关（e.例如，在一个实施例中，波形蛋白、S100 A4、uPAR和埃兹蛋白）（P < 0.05）和不良预后（总生存期：P = 0.018;无病生存期：P = 0.007）。在队列2中，K19 mRNA水平高的HCC表现出较高的Snail、uPAR和MMP 2 mRNA水平（P < 0.05）。K19阳性肝癌的微血管浸润、纤维间质浸润及包膜形成均明显少于K19阴性肝癌（P < 0.05）。K19表达是无病生存率低的独立预测因素（P = 0.032）。结论：K19与肿瘤侵袭性的临床病理特征相关性较好。与K19阴性肝癌相比，K19阳性肝癌中EMT相关蛋白和mRNA表达显著增加，提示其可能通过EMT相关基因的上调而获得更具侵袭性的特征。（肝脏学2011;54：1707-1717）
There is a recently proposed subtype of hepatocellular carcinoma (HCC) that is histologically similar to usual HCC, but characterized by the expression of "stemness"-related markers. A large-scale study on two different cohorts of HCCs was performed to investigate the clinicopathologic features and epithelial-mesenchymal transition (EMT)-related protein expression status of this subtype of HCCs. The expression status of stemness-related (e. g., keratin 19 [K19], cluster of differentiation [CD] 133, epithelial cell adhesion molecule [EpCAM], and c-kit) and EMT-related markers (e. g., snail, S100A4, urokinase plasminogen activator receptor [uPAR], ezrin, vimentin, E-cadherin, and matrix metalloproteinase [MMP]2) were examined using tissue microarrays from cohort 1 HCCs (n = 137). K19 protein expression in cohort 2 HCCs (n = 237) was correlated with the clinicopathologic parameters and messenger RNA (mRNA) levels of K19, uPAR, VIL2, Snail, Slug, and Twist. K19, EpCAM, c-kit, and CD133 positivity were observed in 18.2%, 35.0%, 34.3%, and 24.8%, respectively. K19 was most frequently expressed in combination with at least one other stemness-related marker (92.0%). K19-positive HCCs demonstrated more frequent major vessel invasion and increased tumor size, compared to K19-negative HCCs (P < 0.05). K19 was most significantly associated with EMT-related protein expression (e. g., vimentin, S100A4, uPAR, and ezrin) (P < 0.05) and a poor prognosis (overall survival: P = 0.018; disease-free survival: P = 0.007) in cohort 1. In cohort 2, HCCs with high K19 mRNA levels demonstrated higher mRNA levels of Snail, uPAR, and MMP2 (P < 0.05). K19-positive HCCs demonstrated more frequent microvascular invasion, fibrous stroma, and less tumor-capsule formation, compared to K19-negative HCCs (P < 0.05). K19 expression was a significant independent predictive factor of poor disease-free survival (P = 0.032). Conclusion: K19 was well correlated with clinicopathologic features of tumor aggressiveness, compared to other stemness-related proteins. K19-positive HCCs showed significantly increased EMT-related protein and mRNA expression, suggesting that they may acquire more invasive characteristics, compared to K19-negative HCCs through the up-regulation of EMT-associated genes. (HEPATOLOGY 2011;54:1707-1717)